{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T07:11:07Z","timestamp":1771830667483,"version":"3.50.1"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Persistent pathological pain often induces comorbid depressive-like symptoms, yet the underlying neuronal and molecular mechanisms remain unclear. The nucleus accumbens shell (NAcS) has been implicated in mediating pain sensation and emotional disorders, including depression. However, how it regulates pain-depression comorbidity (PDC) is not well-known. In the present study, we demonstrated that D\n                    <jats:sub>2<\/jats:sub>\n                    -type medium spiny neurons (D\n                    <jats:sub>2<\/jats:sub>\n                    -MSNs) in the NAcS bidirectionally modulated pain and its comorbid behavioral despair measured in the forced swimming test (FST), an effect possibly involving adenosine A\n                    <jats:sub>2A<\/jats:sub>\n                    receptors (A\n                    <jats:sub>2A<\/jats:sub>\n                    Rs). Specifically, acute chemogenetic activation of NAcS D\n                    <jats:sub>2<\/jats:sub>\n                    -MSNs induced thermal\/mechanical pain in na\u00efve mice but did not affect despair-like behavior in the FST, a phenomenon that occurred after repeated activation of these neurons. Conversely, chemogenetic inhibition of NAcS D\n                    <jats:sub>2<\/jats:sub>\n                    -MSNs alleviated spared nerve injury (SNI) induced neuropathic pain and its comorbid behavioral despair. Our immunofluorescent staining revealed a relatively enriched expression of A\n                    <jats:sub>2A<\/jats:sub>\n                    Rs in NAcS D\n                    <jats:sub>2<\/jats:sub>\n                    -MSNs.\n                    <jats:italic>Ex vivo<\/jats:italic>\n                    electrophysiological recordings revealed that activating and inhibiting A\n                    <jats:sub>2A<\/jats:sub>\n                    Rs increased and decreased the neuronal excitability of NAcS D\n                    <jats:sub>2<\/jats:sub>\n                    -MSNs. Consistently, local infusion of the agonist and antagonist of A\n                    <jats:sub>2A<\/jats:sub>\n                    Rs into the NAcS bidirectionally modulated pain and despair-like behaviors in both na\u00efve and SNI mice. Together, these findings demonstrate the functional role of NAcS D\n                    <jats:sub>2<\/jats:sub>\n                    -MSNs in mediating PDC, which was possibly modulated by local A\n                    <jats:sub>2A<\/jats:sub>\n                    Rs, thus providing a potential therapeutic target for PDC.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1759544","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T06:43:36Z","timestamp":1771829016000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Adenosine A2A receptors regulate D2-type medium spiny neurons in the nucleus accumbens to mediate pain and depression comorbidity"],"prefix":"10.3389","volume":"17","author":[{"given":"Dongyu","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, the First Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaona","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pain Management, Lianyungang Clinical College of Nanjing Medical University","place":["Lianyungang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingzhen","family":"Song","sequence":"additional","affiliation":[{"name":"Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University","place":["Xuzhou, China"]},{"name":"Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University","place":["Xuzhou, China"]},{"name":"NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University","place":["Xuzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengyu","family":"Wu","sequence":"additional","affiliation":[{"name":"Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University","place":["Xuzhou, China"]},{"name":"Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University","place":["Xuzhou, China"]},{"name":"NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University","place":["Xuzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongxing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University","place":["Xuzhou, China"]},{"name":"Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University","place":["Xuzhou, China"]},{"name":"NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University","place":["Xuzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun-Li","family":"Cao","sequence":"additional","affiliation":[{"name":"Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Su","family":"Min","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, the First Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e250268","DOI":"10.1001\/jamanetworkopen.2025.0268","article-title":"Prevalence of depression and anxiety among adults with chronic pain: a systematic review and meta-analysis","volume":"8","author":"Aaron","year":"2025","journal-title":"JAMA Netw. 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